Update on protease‐activated receptor 2 in cutaneous barrier, differentiation, tumorigenesis and pigmentation, and its role in related dermatologic diseases

Henehan, Mason; Benedetto, Anna De

doi:10.1111/exd.13936

Cited by 16 publications

(15 citation statements)

References 142 publications

(135 reference statements)

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“…As DSG1, DSC1, and CDSN are the major cleavage targets of KLK5 and KLK7, these enzymes may be directly responsible for the more pronounced degradation of (corneo)desmosomes in SGR and AGR skin [ 14 , 20 ]. In addition, KLKs activate multiple enzymes involved in TJ degradation (e.g., PAR2, matrix metalloproteases) and may be at least partially responsible for TJ weakness in SGR and AGR regions [ 21 , 22 , 23 ]. Moreover, region-specific bacteria and fungi (Propionibacterium and Malassezia on SGR; Corynebacterium, Proteobacteria, and Staphylococcus aureus on AGR skin [ 2 , 17 ]) influence the permeability barrier by producing exogenous serine and cysteine peptidases [ 24 , 25 , 26 , 27 , 28 , 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Regional Differences in the Permeability Barrier of the Skin—Implications in Acantholytic Skin Diseases

Kapitány

Medgyesi

Jenei

et al. 2021

IJMS

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The chemical milieu, microbiota composition, and immune activity show prominent differences in distinct healthy skin areas. The objective of the current study was to compare the major permeability barrier components (stratum corneum and tight junction (TJ)), investigate the distribution of (corneo)desmosomes and TJs, and measure barrier function in healthy sebaceous gland-rich (SGR), apocrine gland-rich (AGR), and gland-poor (GP) skin regions. Molecules involved in cornified envelope (CE) formation, desquamation, and (corneo)desmosome and TJ organization were investigated at the mRNA and protein levels using qRT-PCR and immunohistochemistry. The distribution of junction structures was visualized using confocal microscopy. Transepidermal water loss (TEWL) functional measurements were also performed. CE intracellular structural components were similarly expressed in gland-rich (SGR and AGR) and GP areas. In contrast, significantly lower extracellular protein levels of (corneo)desmosomes (DSG1 and CDSN) and TJs (OCLN and CLDN1) were detected in SGR/AGR areas compared to GP areas. In parallel, kallikrein proteases were significantly higher in gland-rich regions. Moreover, gland-rich areas were characterized by prominently disorganized junction structures ((corneo)desmosomes and TJs) and significantly higher TEWL levels compared to GP skin, which exhibited a regular distribution of junction structures. According to our findings, the permeability barrier of our skin is not uniform. Gland-rich areas are characterized by weaker permeability barrier features compared with GP regions. These findings have important clinical relevance and may explain the preferred localization of acantholytic skin diseases on gland-rich skin regions (e.g., Pemphigus foliaceus, Darier’s disease, and Hailey–Hailey disease).

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Section: Discussionmentioning

confidence: 99%

Regional Differences in the Permeability Barrier of the Skin—Implications in Acantholytic Skin Diseases

Kapitány

Medgyesi

Jenei

et al. 2021

IJMS

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“… 123 Thus, barrier‐targeted therapeutic strategies are likely to open up new possibilities for tailored treatment in pediatric and adult AD. It has been reported that protease‐activated receptor 2 (PAR2) helps promote Th2 inflammation and pruritus 125 . Notably, PAR2 activation reduces the TJ barrier integrity and disrupts claudin‐1 and occludin proteins, which implicates a role of PAR2 in TJ expression and paves the way for exploration of AD pathogenesis (Fig.…”

Section: Tight Junction In Atopic Dermatitismentioning

confidence: 95%

Tight junctions in the development of asthma, chronic rhinosinusitis, atopic dermatitis, eosinophilic esophagitis, and inflammatory bowel diseases

Sugita

Kabashima

2020

Journal of Leukocyte Biology

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This review focuses on recent developments related to asthma, chronic rhinosinusitis, atopic dermatitis (AD), eosinophilic esophagitis, and inflammatory bowel diseases (IBD), with a particular focus on tight junctions (TJs) and their role in the pathogenetic mechanisms of these diseases. Lung, skin, and intestinal surfaces are lined by epithelial cells that interact with environmental factors and immune cells. Therefore, together with the cellular immune system, the epithelium performs a pivotal role as the first line physical barrier against external antigens. Paracellular space is almost exclusively sealed by TJs and is maintained by complex protein-protein interactions. Thus, TJ dysfunction increases paracellular permeability, resulting in enhanced flux across TJs. Epithelial TJ dysfunction also causes immune cell activation and contributes to the pathogenesis of chronic lung, skin, and intestinal inflammation. Characterization of TJ protein alteration is one of the key factors for enhancing our understanding of allergic diseases as well as IBDs. Furthermore, TJ-based epithelial disturbance can promote immune cell behaviors, such as those in dendritic cells, Th2 cells, Th17 cells, and innate lymphoid cells (ILCs), thereby offering new insights into TJ-based targets. The purpose of this review is to illustrate how TJ dysfunction can lead to the disruption of the immune homeostasis in barrier tissues and subsequent inflammation.This review also highlights the various TJ barrier dysfunctions across different organ sites, which would help to develop future drugs to target allergic diseases and IBD.

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“…PAR2 is well expressed in the skin epidermis, and receptor activation becomes prominent in UV-irradiated skin and cultured keratinocytes [ 7 ]. PAR2 is known to exert regulatory functions in the epidermal barrier, keratinocyte differentiation, cutaneous tumorigenesis, inflammation, and pigmentation [ 8 ].Canonical PAR2 signaling includes pathways in which receptor activation stimulates G protein signaling by coupling to the G protein α subunits such as G αi , G αq , and G α12/13 [ 9 ]. In one of the canonical signaling pathways, activation of Gαq leads to it coupling to phospholipase C (PLC), thereby activating the PLC-mediated hydrolysis of phosphatidylinositol 4,5-biphosphate (PIP 2 ) to diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP 3 ).…”

Section: Introductionmentioning

confidence: 99%

Protease-activated receptor 2 induces ROS-mediated inflammation through Akt-mediated NF-κB and FoxO6 modulation during skin photoaging

2021

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Long-term exposure to ultraviolet irradiation to skin leads to deleterious intracellular effects, including reactive oxygen species (ROS) production and inflammatory responses, causing accelerated skin aging. Previous studies have demonstrated that increased expression and activation of protease-activated receptor 2 (PAR2) and Akt is observed in keratinocyte proliferation, suggesting their potential regulatory role in skin photoaging. However, the specific underlying molecular mechanism of PAR2 and the Akt/NF-κB/FoxO6-mediated signaling pathway is not clearly defined. In this study, we first used the UVB-irradiated photoaged skin of hairless mice and observed an increase in PAR2 and Gαq expression and PI3-kinase/Akt, NF-κB, and suppressed FoxO6. Consequently, increased levels of proinflammatory cytokines and decreased levels of antioxidant MnSOD was observed. Next, to investigate PAR2-specific roles in inflammation and oxidative stress, we used photoaged hairless mice topically applied with PAR2 antagonist GB83 and photoaged PAR2 knockout mice. PAR2 inhibition and deletion significantly suppressed inflammatory and oxidative stress levels, which were associated with decreased IL-6 and IL-1β levels and increased MnSOD levels, respectively. Furthermore, NF-κB phosphorylation and decreased FoxO6 was reduced by PAR2 inhibition and deletion in vivo . To confirm the in vivo results, we conducted PAR2 knockdown and overexpression in UVB-irradiated HaCaT cells. In PAR2 knockdown cells by si-PAR2 treatment, it suppressed Akt/NF-κB and increased FoxO6, whereas PAR2 overexpression reversed these effects and subsequently modulated proinflammatory target genes. Collectively, our data define that PAR2 induces oxidative stress and inflammation through Akt-mediated phosphorylation of NF-κB (Ser536) and FoxO6 (Ser184), which could be a critical upstream regulatory mechanism in ROS-mediated inflammatory response.

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Update on protease‐activated receptor 2 in cutaneous barrier, differentiation, tumorigenesis and pigmentation, and its role in related dermatologic diseases

Cited by 16 publications

References 142 publications

Regional Differences in the Permeability Barrier of the Skin—Implications in Acantholytic Skin Diseases

Regional Differences in the Permeability Barrier of the Skin—Implications in Acantholytic Skin Diseases

Tight junctions in the development of asthma, chronic rhinosinusitis, atopic dermatitis, eosinophilic esophagitis, and inflammatory bowel diseases

Protease-activated receptor 2 induces ROS-mediated inflammation through Akt-mediated NF-κB and FoxO6 modulation during skin photoaging

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